The CCL20-CCR6 axis predominantly drives IL-17-mediated psoriasis while modestly contributing to papain-induced type 2 inflammation.

Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis (AD) are characterized by immune dysregulation. The chemokine CCL20 and its unique receptor CCR6 are upregulated in lesional skin of patients with both psoriasis and AD. To investigate their roles in disease pathogenesis, CCL20- and CCR6-deficient (KO) mice were generated. In an imiquimod (IMQ)-induced psoriasis model, clinical scores were significantly reduced in both CCL20- and CCR6-KO mice compared with wild-type (WT) mice. Moreover, the expression of Th17-related cytokines and the migration of γδlow+ T cells into the epidermis were markedly decreased in IMQ-treated KO mice. In contrast, in a papain-induced AD model, KO mice exhibited an approximately 40% reduction in disease severity compared with WT controls. Papain-treated KO mice showed significant reductions in type 2-associated responses, including IL-4 production, IgE levels, and mast cell accumulation, whereas effects on other immune cell populations were limited. Collectively, these findings indicate that the CCL20-CCR6 axis predominantly drives psoriasis pathogenesis, whereas its contribution to papain-induced AD-like inflammation is comparatively limited. These results highlight the CCL20-CCR6 axis as a key regulator of IL-17-driven skin inflammation and a potential therapeutic target, particularly in psoriasis.